Myelin Antigen-Specific CD8+ T Cells Are Encephalitogenic and Produce Severe Disease in C57BL/6 Mice

Sun, Deming; Whitaker, John N.; Huang, Zhigang; Liu, Di; Coleclough, Christopher; Wekerle, Hartmut; Raine, Cedric S.

doi:10.4049/jimmunol.166.12.7579

Cited by 397 publications

(315 citation statements)

References 50 publications

Supporting

Mentioning

293

Contrasting

Unclassified

Order By: Relevance

“…Autoreactive CD8 ϩ T cells have also been implicated as potent effector cells in several animal models of autoimmune diseases including EAE. Adoptive transfer studies of CD8 ϩ T cells isolated from animals with EAE have successfully propagated the disease to naïve recipients (24,25). Mixed results have been reported in EAE studies in animals lacking CD8 ϩ T cells.…”

mentioning

confidence: 75%

CD8⁺T cells are not necessary for 1α,25-dihydroxyvitamin D₃to suppress experimental autoimmune encephalomyelitis in mice

Meehan

DeLuca

2002

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

In addition to its role in calcium and phosphorous homeostasis, 1␣,25-dihydroxyvitamin D3 [1,25-(OH)2D3] appears to be a modulator of the immune system. Administration of 1,25-(OH) 2D3 prevents disease in several autoimmune animal models, including experimental autoimmune encephalomyelitis (EAE). The vitamin D receptor is believed to mediate this activity. Among cells of the immune system, CD8 ؉ T cells have the highest levels of the vitamin D receptor. Because CD8 ؉ T cells have been implicated as both suppressors and effectors of the inflammation associated with multiple sclerosis and EAE, we examined the question of whether the 1,25-(OH) 2D3 suppression of EAE occurs through a CD8 ؉ T cell-dependent mechanism. To test this hypothesis, mice that are homozygous knockouts for the ␣ chain of the CD8 receptor and have been characterized as lacking functional CD8 ؉ T cells (CD8 ؉ ؊͞؊) were provided 1,25-(OH)2D3 in their diet before EAE induction. Although CD8 ؉ ؊͞؊ mice fed the same diet lacking 1,25-(OH) 2D3 have a high incidence of EAE, EAE did not occur in CD8 ؉ ؊͞؊ mice fed the diet containing 1,25-(OH)2D3. We conclude that CD8 ؉ T cells neither are needed nor do they play a role in the prevention of EAE by 1,25-(OH) 2D3.M ultiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system that is the leading cause of disease-associated neurological disability in western countries (1). This disease is characterized by destruction of the myelin sheaths that surround axons in the central nervous system and ultimately results in numerous neurological defects that manifest in symptoms including fatigue, limb spasticity, bladder dysfunction, and muscle weakness so severe that death is sometimes the result (2, 3). This inflammation is caused by either a breakdown in immunological self tolerance and͞or an infection that triggers central nervous system-specific T cells to form inflammatory lesions. Although very little is known about the triggering event for MS, it is clear that both environmental and genetic factors are involved (4). In examining environmental factors, the geographical distribution of MS must be considered. A north-to-south gradient of higher-to-lower MS incidence in the northern hemisphere has been demonstrated in epidemiology studies, whereas a similar gradient running south to north has been observed in the southern hemisphere (5, 6). In 1974, P. Goldberg noted that this MS incidence gradient correlated with the incidence of vitamin D deficiency in temperate regions, relative to equatorial regions (7). Further studies demonstrated a lower MS incidence in temperate areas where vitamin D is abundant because of increased sun exposure, high altitudes, or diets rich in fish oils (8)(9)(10)(11).Insights into the disease course of MS have been found by using the animal model experimental autoimmune encephalomyelitis (EAE). EAE is a CD4 ϩ T cell-mediated inflammatory demylenating disease that shares many similarities with MS and is induced by injecting an antigen such as myelin basic pro...

show abstract

mentioning

confidence: 75%

CD8⁺T cells are not necessary for 1α,25-dihydroxyvitamin D₃to suppress experimental autoimmune encephalomyelitis in mice

Meehan

DeLuca

2002

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Huseby et al have demonstrated that adoptive transfer of H-2K k -restricted CD8 T cells specific for MBP [79][80][81][82][83][84][85][86][87] induces clinical experimental autoimmune encephalomyelitis (EAE) in C3H mice, reproducing features of MS lesions usually not observed in CD4 T cell-driven EAE [56]. Furthermore, adoptive transfer of MOG specific CD8 T cells induces progressive EAE in C57BL/6 mice, independent of CD4 T cells [57]. The adoptive transfer of H-2D b -restricted CD8 T cells specific for the short MOG 37-46 peptide also induces EAE into C57Bl/6 recipients [58].…”

Section: Cd8 T Cells In Animal Models Of Msmentioning

confidence: 99%

Role of CD8 T cell subsets in the pathogenesis of multiple sclerosis

et al. 2011

View full text Add to dashboard Cite

a b s t r a c tMultiple sclerosis (MS) is an immune-mediated disease of the central nervous system leading to demyelination and axonal/neuronal loss. Cumulating evidence points to a key role for CD8 T cells in this disabling disease. Oligoclonal CD8 T cells reside in demyelinating plaques where they are likely to contribute to tissue destruction. Histopathological analyses and compelling observations from animal models indicate that cytotoxic CD8 T cells target neural cell populations with the potential of causing lesions reminiscent of MS. However, CD8 T cell differentiation results in several subsets of effector CD8 T cells that could be differentially implicated in the mechanisms contributing to tissue damage. Moreover CD8 regulatory T cells arise as important populations involved in restoring immune homoeostasis and in maintaining immune privileged sites. Here we examine the current literature pertaining to the role of CD8 effector and regulatory T cell subsets in the pathogenesis of MS.

show abstract

“…Chronic relapsing or nonrelapsing forms of EAE can be induced in rodents by active immunization with myelin Ags such as myelin oligodendrocyte glycoprotein (MOG) (1) or by passive transfer of MOGspecific CD4 ϩ or CD8 ϩ T cells and anti-MOG Abs (2,3). The pathology of EAE is well described, differs between models, but is generally characterized by increased permeability of the bloodbrain barrier, perivascular inflammatory infiltrates comprised of T cells, B cells, macrophages, and granulocytes, and demyelination leading to an ascending paralysis of the extremities.…”

Section: E Xperimental Autoimmune Encephalomyelitis (Eae)mentioning

confidence: 99%

Expression of the Long Form of Human FLIP by Retroviral Gene Transfer of Hemopoietic Stem Cells Exacerbates Experimental Autoimmune Encephalomyelitis

Djerbi

Abdul-Majid

Abedi‐Valugerdi

et al. 2003

The Journal of Immunology

View full text Add to dashboard Cite

Subsidence of inflammation and clinical recovery in experimental autoimmune encephalomyelitis (EAE) is postulated to involve apoptosis of inflammatory cells. To test this concept, we examined the effects of overexpressing the long form of human FLICE-inhibitory protein, a potent inhibitor of death receptor-mediated apoptosis, in myelin oligodendrocyte glycoprotein-induced EAE in DBA/1 mice. We found that overexpression of the long form of human FLICE-inhibitory protein by retroviral gene transfer of hemopoietic stem cells led to a clinically more severe EAE in these mice compared with control mice receiving the retroviral vector alone. The exacerbated disease was evident by an enhanced and prolonged inflammatory reaction in the CNS of these animals compared with control mice. The acute phase of EAE was characterized by a massive infiltration of macrophages and granulocytes and a simultaneous increase in TNF-α production in the CNS. In the chronic phase of the disease, there was a prolonged inflammatory response in the form of persistent CD4+ T and B cells in the CNS and a peripheral Th1 cytokine bias caused by elevated levels of IFN-γ and reduced levels of IL-4 in the spleen. Our findings demonstrate that death receptor-mediated apoptosis can be important in the pathogenesis of EAE and further emphasize the need for effective apoptotic elimination of inflammatory cells to achieve disease remission.

show abstract

Myelin Antigen-Specific CD8+ T Cells Are Encephalitogenic and Produce Severe Disease in C57BL/6 Mice

Cited by 397 publications

References 50 publications

CD8⁺T cells are not necessary for 1α,25-dihydroxyvitamin D₃to suppress experimental autoimmune encephalomyelitis in mice

CD8⁺T cells are not necessary for 1α,25-dihydroxyvitamin D₃to suppress experimental autoimmune encephalomyelitis in mice

Role of CD8 T cell subsets in the pathogenesis of multiple sclerosis

Expression of the Long Form of Human FLIP by Retroviral Gene Transfer of Hemopoietic Stem Cells Exacerbates Experimental Autoimmune Encephalomyelitis

Contact Info

Product

Resources

About

Myelin Antigen-Specific CD8+ T Cells Are Encephalitogenic and Produce Severe Disease in C57BL/6 Mice

Cited by 397 publications

References 50 publications

CD8+T cells are not necessary for 1α,25-dihydroxyvitamin D3to suppress experimental autoimmune encephalomyelitis in mice

CD8+T cells are not necessary for 1α,25-dihydroxyvitamin D3to suppress experimental autoimmune encephalomyelitis in mice

Role of CD8 T cell subsets in the pathogenesis of multiple sclerosis

Expression of the Long Form of Human FLIP by Retroviral Gene Transfer of Hemopoietic Stem Cells Exacerbates Experimental Autoimmune Encephalomyelitis

Contact Info

Product

Resources

About

CD8⁺T cells are not necessary for 1α,25-dihydroxyvitamin D₃to suppress experimental autoimmune encephalomyelitis in mice

CD8⁺T cells are not necessary for 1α,25-dihydroxyvitamin D₃to suppress experimental autoimmune encephalomyelitis in mice